SULF1作为特发性肺纤维化与肺腺癌共同基因的鉴定及其生物学功能分析

背景和目的 特发性肺纤维化（idiopathic pulmonary fibrosis, IPF）是一种原因不明的慢性、进行性、间质性肺疾病，确诊后中位生存期为3-5年。IPF与肺癌风险增加有关。因此，探索IPF和肺腺癌的关键共同致病基因和分子通路，对开发IPF合并肺腺癌的新治疗手段和个性化精准治疗策略的制定具有重要意义。方法 利用基因表达综合（Gene Expression Omnibus, GEO）数据库中公开的IPF和肺腺癌基因表达数据集进行生物信息学分析。使用加权基因共表达网络分析识别涉及两种疾病进程的共同基因，进而功能富集分析。随后，联合额外数据集鉴定两种疾病的核心共同基因。并通过癌症基因组图谱计划（The Cancer Genome Atlas, TCGA）数据库和单细胞RNA测序数据集，分析核心共同基因与患者预后的关系，并评估其在肺腺癌中的表达模式、临床相关性、遗传特征和免疫相关功能。最后通过药物数据库筛选出相关的潜在治疗药物。结果 两者之间有529个共同致病基因。其中，SULF1作为核心共同致病基因与患者预后不良相关，其在肺腺癌组织中的表达水平显著升高，同时与高突变频率、显著基因组异质性以及抑制性免疫微环境相关。随后的单细胞分析发现SULF1高表达主要源于肿瘤相关成纤维细胞。SULF1表达与肿瘤药物敏感性变化相关，并筛选出与靶向SULF1高表达成纤维细胞相关的潜在小分子药物。结论 本研究鉴别出IPF和肺腺癌之间的共同分子途径和核心基因，其中SULF1可能作为两种疾病的潜在生物标志物和治疗靶点。

strategies for IPF combined with lung cancer.Methods Bioinformatics analysis was conducted using publicly available gene expression datasets of IPF and LUAD from the Gene Expression Omnibus (GEO) database.Weighted gene co-expression network analysis was employed to identify common genes involved in the progression of both diseases, followed by functional enrichment analysis.Subsequently, additional datasets were used to pinpoint the core shared genes between the two diseases.The relationship between core shared genes and prognosis, as well as their expression patterns, clinical relevance, genetic characteristics, and immune-related functions in LUAD, were analyzed using The Cancer Genome Atlas (TCGA)   database and single-cell RNA sequencing datasets.Finally, potential therapeutic drugs related to the identified genes were screened through drug databases.Results A total of 529 shared genes between IPF and LUAD were identified.Among them, SULF1 emerged as a core shared gene associated with poor prognosis.It exhibited significantly elevated expression levels in LUAD tissues, concomitant with high mutation rates, genomic heterogeneity, and an immunosuppressive microenvironment.Subsequent single-cell RNA-seq analysis revealed that the high expression of SULF1 primarily originated from tumor-associated fibroblasts.This study further demonstrated an association between SULF1 expression and tumor drug sensitivity, and it identified potential small-molecule drugs targeting SULF1 highly expressed fibroblasts.Conclusions This study identified a set of shared molecular pathways and core genes between IPF and LUAD.Notably, SULF1 may serve as a potential immune-related biomarker and therapeutic target for both diseases.
Fig 1 I dentif ic ation of weighted gene coe x p r essi o n m o dul es i n I P F a n d LUA D. A : Clus ter dendro gram of co-expressed genes i n I P F ; B : H e a t m a p o f m o d u l e -t r a i t relationships in IPF; C: Clus ter dendro gram of co-expressed genes in LUAD; D: Heatmap o f m o d u l e -t r a i t relationships in LUAD; E-H: Dot plots showing gene significance and module membership in selected modules.C t r l : c o n t r o l ; I P F : idiopathic pulmonary f ib r osis; LUAD: lu n g enocarcinoma.
Fig 2 Identification and functional analysis of shared genes in IPF and LUAD.A: Venn diagram of the shared genes between the four selected modules; B: PPI network of the shared genes; C: Network plot showing the GO enrichment pathways; D: Network plot showing the KEGG enrichment pathways.PPI: protein-protein interaction; GO: Gene Ontology; KEGG: Kyoto Encyclopedia of Genes and Genomes.

Fig 3
Fig 3 Identification of SULF1 as a core shared gene.A: Volcano map of the DEGs in IPF dataset; B: Volcano map of the DEGs in LUAD dataset; C: Venn diagram of the core shared genes between the share d genes identif ie d in WGCNA and DEGS of the additional datasets; D-I: Survival curves using the Kaplan-Meier plotter are shown for OS and PFS; J: Expression of SULF1 in LUAD compared to normal tissues in the GEPIA dat ab ase; K-P : SU L F1 e x p r e s s i o n a m o n g different groups of patients based on clinical parameters using the UALCAN database; Q: Promoter methylation of SULF1 based on the UALCAN database; R, S: SULF1 protein expression among different groups of patients based on clinical p ar am e te r s usin g th e UALC AN database; T: Expression of SULF1 in IPF lungs compared to control tissues in GSE32537 dataset; U: ROC curve analysis of SULF1 expression i n I P F. D E G s : d i f f e r e n t i a l l y e x p r e s s e d g e n e s ; O S : o v e r a l l sur vival; PFS: progression -free survival; ROC: receiver operator characteristic.*P<0.05;**P<0.01;***P<0.001;****P<0.0001.

Fig 6 Fig 7
Fig 5 SULF1 and the tumor microenvironment in LUAD.A: Box plots showing the immune cell infiltration patterns between high and low expression groups; B: Expression of immune checkpoint inhibitors between SULF1-high and SULF1-low groups of LUAD; C: Bubble plot showing the differential pathway profiles between the high and low SULF1 expression groups of LUAD.**P<0.01;***P<0.001;****P<0.0001.